Stroke is a leading cause of disability in the United States and poses a significant burden to Veterans. The effectiveness of current intervention approaches is limited and many individuals following stroke live with persistent functional, cognitive and psychological impairments that significantly reduce long-term quality of life. The prevalence of post-stroke disability coupled with reduced stroke mortality rates reflects an increasing need to develop effective rehabilitation strategies aimed at reducing disability and improving quality of life for Veteran stroke survivors. Aerobic exercise (AEx) promotes numerous functional, cognitive, and psychological benefits. Additionally, AEx may enhance neuroplasticity through increases in circulating brain-derived neurotrophic factor (BDNF) and corticomotor excitability (CME). Emerging evidence also supports the use of AEx as a priming tool to enhance motor outcomes following targeted rehabilitation. Our conceptual framework involves priming with AEx prior to targeted motor rehabilitation to enhance the ‘neuroplastic environment” and make the brain more amenable to adaptation, thereby enhancing response to rehabilitation. Specifically, we propose to pair AEx with an upper extremity virtual reality rehabilitation game called Duck Duck Punch (DDP), developed by our team (Co-mentor: Woodbury) as the platform for examining the adjunctive potential of AEx. Therefore the primary aim of this proposal is to evaluate the priming effects of AEx on a motor rehabilitation intervention (i.e. DDP) for chronic stroke survivors. This will be accomplished by examining a cohort of stroke survivors who will be randomly assigned to receive 8 weeks (3 sessions/week) of DDP preceded by either 15 minutes of AEx (AEx+DDP) or a stretching control (CON+DDP). Assessment of physical function before and after the intervention will provide insight into the ability of AEx to enhance the response to motor rehabilitation. The secondary aim of this proposal is to gain insight into the mechanisms that underlie the priming effects of AEx through assessment of circulating BDNF and CME. Additionally, since stroke survivors often experience cognitive and psychological impairments we will also explore the influence of cognitive and psychological function on response to AEx+DDP. A potentially exciting possibility is that AEx facilitates an enhanced neuroplastic environment, which fosters improved function in a variety of aspects of stroke recovery including physical, cognitive, and psychological function. This proposal will be supported by the infrastructure and resources provided by the South Carolina Research Center for Recovery from Stroke (NIH P20 GM109040). Furthermore, the combination of the Ralph H. Johnson VA Medical Center and its affiliated academic institution, Medical University of South Carolina is uniquely positioned to fill the aforementioned gap in understanding for several reasons: 1) Charleston, South Carolina has one of the h...